Mapping out the pathways in severe asthma

Einstein once said that “If you always do what you always did, you will always get what you always got.” A MedImmune scientist is likely to tell you: That’s a plain fact. And if ever there were proof, our investigational respiratory biologics portfolio would be it.

Asthma affects 315 million individuals worldwide1, yet no two patients are ever exactly alike. In addressing this heterogeneous disease—with complex biology and various immunological disease drivers2,3—MedImmune researchers have stepped out of the box to address an important unmet need. We are innovating to target specific biologic treatments to patient types, so that we might optimise individual responses to treatment.

As we prepare for this year’s European Respiratory Society (ERS) conference, held in Milan, Italy, September 9 - 13, we thought we’d shift the focus from talking data, endpoints, and outcomes to digging back into the early science behind this portfolio — and how following the science has opened the door for new discovery.

In this Q&A, Roland Kolbeck, PhD, MedImmune’s VP, R&D, Respiratory, Inflammation, and Autoimmunity (RIA) shares his thoughts on the development of these important investigational biologics.

Q: Why is the early science important in biologics development?

A: Within the larger context of our RIA research and development, our focus is on the biological pathways that characterise conditions—whether asthma or chronic obstructive pulmonary disease (COPD), in the case of respiratory, or other inflammatory and autoimmune illnesses. Investigating these pathways and their molecular originations enables a better understanding of disease; this is our highest priority. Without this early work and the knowledge that it reveals—particularly in this era of personalised medicine—drug development today would continue along a path of “one size fits all” medicine. Early science moves us toward disruptive breakthroughs in treatment.

Q: How has the early science “personalised” respiratory biologics?

A: Inflammatory diseases—asthma and COPD, for example—encompass several distinct patient phenotypes, and these are characterised by the shared presence of cellular and molecular biomarkers.3 When we are able to link these biomarkers with clinical phenotypes, this significantly shifts and advances our understanding of pathophysiology; in turn, facilitating the clinical development of biologics. For example, today we know that eosinophils are a feature in the exacerbations of some patients with asthma, and particularly those with severe, uncontrolled asthma. We also know that interleukin (IL)-5 induces eosinophilic airway inflammation.4 We use this knowledge to drive our investigations into potential therapeutic options.

Q: What are you learning about other respiratory disease pathways, and how is this informing future drug development?

A: We are learning more about thymic stromal lymphopoietin, or TSLP and exploring new approaches to address its role in respiratory disease. TSLP is a pro-inflammatory cytokine, a signalling protein that plays a key role in the inflammation cascade that triggers severe asthma.5 When an asthma patient responds to allergens, viruses and other pathogens in the lung, there are multiple inflammatory pathways through which TSLP can drive a response, and that starts from way upstream in the respiratory system. In fact – TSLP acts like an upstream master switch.

Our investigations seek to understand how targeting pathways like TSLP may play a role in helping a broad population of patients with severe asthma.

Q: What do you hope most for in your early science efforts?

A: When we look at respiratory conditions like asthma and COPD, we see remarkable heterogeneity. In severe patients, we also see suboptimal control of symptoms through existing therapies that include inhaled corticosteroids (ICS).6 This means that there remains a substantial unmet need for treatments that improve symptom control and slow disease progression. The goal of early science is to understand the subtleties and diversity of disease, and identify specific biomarkers and pathways that will enable the development of potent biologics that hits these pathways, most particularly for patients who may not have other options. We still have much to learn, but by scrutinising and following the early science at the cellular and molecular level, we are several steps closer in our efforts.

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